Use of an aromatase inhibitor for the treatment of hypogonadism and related diseases

ABSTRACT

The aromatase inhibitor 4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile increases testosterone levels and treats hypogonadism and related diseases. A particular dosing regimen is disclosed as well as pharmaceutical compositions comprising said of 4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile, optionally in combination with other active ingredients and kits comprising the pharmaceutical compositions.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/342,810 filed on Mar. 5, 2014, which is the National Stage ofInternational Application No. PCT/US2012/053844 filed on Sep. 6, 2012,which claimed priority to U.S. Provisional Application Ser. No.61/532,459, filed on Sep. 8, 2011, and to U.S. Provisional ApplicationSer. No. 61/638,588, filed on Apr. 26, 2012, all of which areincorporated by reference in their entirety.

FIELD OF THE INVENTION

This invention relates to a method of increasing testosterone levels andtreating hypogonadism and related diseases with the aromatase inhibitor4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]-bisbenzonitrile. Thepresent invention further relates to a method of increasing testosteronelevels and treating hypogonadism and related diseases with the aromataseinhibitor4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]-bisbenzonitrile in aparticular dosing regimen. The invention also relates to pharmaceuticalcompositions comprising said aromatase inhibitor4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]-bisbenzonitrile,optionally in combination with other active ingredients. Furthermore,the present invention relates to kits comprising said pharmaceuticalcompositions together with instructions how to administer them.

BACKGROUND OF THE INVENTION

The enzyme aromatase (CYP 19) is highly expressed in adipose tissue,where it converts testosterone to estradiol. In human overweight orobesity, excess adipose tissue is associated with excess aromataseactivity, which in turn results in higher levels of estradiol in bothmen and women. In overweight and obese men, the relative excess ofestradiol can feed back to the hypothalamic pituitary axis, suppressinggonadotropin secretion and thereby suppressing testicular testosteroneproduction as well as spermatogenesis. Thus, severe obesity isassociated with relative androgen deficiency in men. This condition canbe called OHH or obese hypogonadotropic hypogonadism or hypogonadotropichypogonadism in obese men.

In the 1999-2002 National Health and Nutrition Examination Survey dataset, 27.5% of men over the age of 20 in the United States had a BodyMass Index (BMI) above 30 kg/m². The prevalence of obesity is expectedto continue to increase in the United States, and in both developed anddeveloping countries around the world. In one study of 160 men referredfor medical or surgical treatment of obesity, hypogonadotropichypogonadism was present in 36% overall. In this study, the prevalenceof hypogonadotropic hypogonadism rose linearly from 7.4% in those with aBMI of 30-35 kg/m² to 59.2% in those with a BMI above 50 kg/m² [Hofstra,et al 2008]. Based on the prevalence of obesity, we estimate that up to1.5 million men in the US and 1 million men in Europe would haveandrogen deficiency due to hypogonadotropic hypogonadism.

The consequences of testosterone deficiency are many, including symptomsof decreased libido, decreased spontaneous erections, decreasedfertility, loss of body hair and reduced shaving, low bone mineraldensity, increased risk of fractures, decreased muscle mass and strengthand fatigue [Bhasin, et al 2006]. In addition, more recent studies havedemonstrated that testosterone deficiency in older men and in men withobesity is also associated with metabolic abnormalities includinginsulin resistance, glucose intolerance, and lipid abnormalities,contributing to an increased incidence of metabolic syndrome, and likelyincreased risk of cardiovascular disease. In one study, up to 15% ofdiabetic men had clear hypogonadism (testosterone <300 ng/dL or <8nmol/L) and up to 50% had testosterone in the lower range of normal (<12nmol/L or <450 ng/dL) [Kapoor, et al 2006 and 2007]. An association hasbeen established between low testosterone levels and variouscardiovascular risk factors. Recent epidemiological studies have alsolinked low testosterone with cardiovascular mortality [Maggio et al.2009].

Guidelines for the treatment of male hypogonadism have been developed byseveral organizations, including the Endocrine Society of the UnitedStates stating that “We recommend testosterone therapy for symptomaticmen with androgen deficiency, who have low testosterone levels, toinduce and maintain secondary sex characteristics and to improve theirsexual function, sense of well-being, muscle mass and strength, and bonemineral density” [Bhasin, et al 2006]. Replacement of testosterone istypically recommended by either intramuscular or transdermal routes asthe standard of care for men with documented hypogonadism (testosterone<300 ng/dL associated with symptoms of low testosterone) and cannormalize libido, muscle mass and strength [Bhasin, et al 2006]. Inaddition, testosterone replacement improves insulin resistance in menwith hypogonadism [Naharci, et al 2007].

Next to overweight and obesity and its associated excess aromataseactivity, other causes of hypogonadism in men include primary testicularfailure, which may be due to endogenous defects or acquired due totrauma, infection, or chemo- or radiation therapy, and secondaryfailures with suppression of gonadotropins that may be due to stress,concomitant diseases, or hypothalamic pituitary disorders.

Current therapies for testosterone deficiency are limited. Mosthypogonadal men are treated with intramuscular injections oftestosterone every 2 to 4 weeks, typically requiring a visit to a healthcare provider. Some men choose testosterone gels or patches that areusually applied daily. Men with OHH desiring fertility may be treatedwith intramuscular or subcutaneous injections of HCG or gonadotropins.There are various complications of testosterone replacement which mayinclude gynecomastia due to the excessive conversion of exogenoustestosterone to estradiol, infertility due to suppression ofgonadotropins, mood swings due to the rise and fall of testosteroneafter intramuscular injections, and injection site or application siteirritation. Excess testosterone can lead to polycythemia(erythrocytosis), prostate enlargement, sleep apnea, and worsening heartfailure, in addition to aggressiveness. The Endocrine Society recommends“against starting testosterone therapy in patients with breast orprostate cancer, a palpable prostate nodule or induration orprostate-specific antigen greater than 3 ng/ml without furtherurological evaluation, erythrocytosis (hematocrit >50%), hyperviscosity,untreated obstructive sleep apnea, severe lower urinary tract symptomswith International Prostate Symptom Score (IPSS) [Barry, et al 1992]greater than 19, or class III or IV heart failure.”, and that “menreceiving testosterone therapy should be monitored using a standardizedplan” [Bhasin, et al 2006].

Oral androgen therapies are generally contraindicated because of firstpass hepatic effects that dramatically suppress HDL, increasethrombogenic factors, and often cause liver function abnormalities.These hepatic effects of androgens have also so far limited the clinicalutility of selective androgen receptor modulators (SARMs).

Some commercially available aromatase inhibitors have also been testedfor efficacy in hypogonadal men in a few, small proof of conceptstudies. Letrozole, given at doses of 2.5 mg weekly, increased totaltestosterone into the normal range, suppressed total estradiol, andincreased LH and FSH in 12 OHH men [de Boer, et al 2005, Loves, et al2008]. At this fixed dosing interval, free testosterone rose above thenormal range in approximately half of the subjects. Other investigatorshave assessed the effects of aromatase inhibitors (letrozole [de Boer,et al 2005, Lapauw, et al 2009, Loves, et al 2008] CGS 20267 [Trunet, etal 1993] and anastrozole [Medras, et al 2007]) in uncontrolled studies.

One potential draw-back of all clinical studies conducted so far is thatthe aromatase inhibitors used in studies—anastrozole and letrozole—weredeveloped for the treatment of hormone dependent cancers such as breastcancer in post-menopausal women and might therefore not be optimallysuitable to treat hypogonadism in male patients, in particular in viewof the optimal dosages and dosing regimen, and the potential sideeffects. Dosages and dosing regimens assessed so far in the clinicaltrials comprised the weekly administration of 2.5 mg or 1 mg of therespective aromatase inhibitor for the treatment of hypogonadism—whichcorresponds to the dosages used for adjuvant treatment of postmenopausalwomen with hormone receptor positive early breast cancer, but not anoptimized treatment regimen for hypogonadism.

Indeed, human PK/PD studies of marketed aromatase inhibitors in men withhypogonadism have shown that e.g. letrozole at a 2.5 mg weekly doseresulted in excessive free testosterone levels in approximately half thesubjects [Loves, et al, 2008]. There have been no studies so far tofully assess the effects of aromatase inhibitors on testosterone levelsand how to actually achieve normalization of testosterone levels in menwith hypogonadism.

Thus, optimized treatment regimens providing the relief of thetestosterone deficiency driven symptoms of hypogonadism with minimalside effects are required. The development of an aromatase inhibitorespecially suited for male patients with decreased testosterone levelswould provide a novel treatment option for this so far insufficientlytargeted disease.

In addition to the clinically approved non-steroidal aromataseInhibitors anastrozole, letrozole and fadrozole, which are approved forthe treatment of hormone dependent breast cancer by daily administrationof dosages in the mg range, several other aromatase inhibitors have beendescribed in the patent and scientific literature. One of thesecompounds is the aromatase inhibitor4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile, alsoknown as4-[α-4-Cyanophenyl)-α-fluoro-1-(1,2,4-triazolyl)methyl]-benzonitrile orCGP47645, first described in 1992 [EP 490 816 and U.S. Pat. No.5,637,605], having the following structural formula

CGP47645 is a fluoro-derivative of letrozole with a prolonged durationof action. Preliminary in-vitro and in-vivo experiments with thiscompound in rats and monkeys showed a similar up to 10 fold higherpotency of aromatase inhibition as letrozole, and demonstrated thepotential for less than daily treatment regimen. A once weeklyadministration of 3 mg/kg of CGP47645 was considered as an effectivedose achieving medical castration in adult female rats [Batzl-Hartmannet al, 1994]. It was concluded that the half-life of CGP47645 is longenough to maintain endocrine efficacy similar to that of ovariectomywith a once-weekly dosing schedule [Bhatnagar et al, 1996]. However, nofurther studies of this drug compound have been carried out and itspotential for the treatment of hormone dependent cancers or otherdiseases such as endometriosis was never investigated.

Currently, there are no oral pharmacological treatment regimens approvedto treat hypogonadism and/or testosterone deficiency in obese malepatients in the US and most other countries. As set out above,currently, testosterone, HCG or gonadotropin injections are so far theonly option for these patients. Therefore, there is an important unmetmedical need in this population for the development of a pharmacologicaltreatment that reduces the disorders and symptoms associated withtestosterone deficiency.

In particular, an oral therapy that normalizes systemic testosterone,but does not significantly increase local hepatic exposure to androgenswould be highly desirable. In addition, it would be desirable to have atreatment regimen available achieving a more physiologic testosteronereplacement.

In consideration of all problems and disadvantages connected with the sofar known treatment options for male hypogonadism and testosteronedeficiency, in particular hypogonadotropic hypogonadism in obese oroverweight men, it would be highly advantageous to provide a newtreatment option overcoming the aforementioned drawbacks and indeedproviding relief or at least improvement for these patients.

SUMMARY OF THE INVENTION

Accordingly, in a first aspect the present invention relates to thecompound 4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrilefor use in the treatment of a male patient in need of increasedtestosterone levels.

In one embodiment said male patient is overweight or obese.

In a second aspect the present invention relates to the compound4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile for usein the treatment of hypogonadism in a male patient.

In a third aspect, the present invention relates to the compound4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile for usein the treatment of hypogonadism in an overweight or obese male patient.

In a fourth aspect, the present invention relates to the compound4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile for usein the treatment of hypogonadotropic hypogonadism in a male patient.

In a further aspect, the present invention relates to the compound4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile for usein the treatment of hypogonadotropic hypogonadism in an overweight orobese male patient.

In a further aspect, the present invention relates to the compound4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile forincreasing, preferably normalizing testosterone levels in a male patientwith hypogonadism or hypogonadotropic hypogonadism, preferably in anoverweight or obese male patient with hypogonadism or hypogonadotropichypogonadism.

In a further aspect, the present invention relates to the compound4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile for usein the treatment of a male patient in need of increased testosteronelevels, wherein the compound is provided in a form comprising from about0.0005 mg to about 5.0 mg, preferably from about 0.0005 mg to about 2.0mg 4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile perdose and is for administration according to a dosing regimen having adosing periodicity ranging from about once daily to about once every 60days.

In a further aspect the present invention relates to the use of4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile for themanufacture of a medicament for the treatment of a male patient in needof increased testosterone levels.

In a further aspect the present invention relates to the use of4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile for themanufacture of a medicament for the increasing, preferably normalizingtestosterone levels in an overweight or obese male patient withhypogonadotropic hypogonadism.

A further aspect of the present invention relates to the use of4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile for themanufacture of a medicament for the treatment of a male patient in needof increased testosterone levels, wherein the compound is provided in aform comprising from about 0.0005 mg to about 5.0 mg, preferably fromabout 0.0005 mg to about 2.0 mg4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile per doseand is for administration according to a dosing regimen having a dosingperiodicity ranging from about once daily to about once every 60 days.

In a further aspect the present invention relates to an oralpharmaceutical composition comprising from about 0.0005 mg to about 5.0mg, preferably from about 0.0005 mg to about 2.0 mg4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile per dose,optionally in combination with one or more pharmaceutically acceptableexcipients.

According to a further aspect of the invention there is provided a kitof parts comprising (i) such a pharmaceutical composition comprising4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile,optionally in combination with one or more pharmaceutically acceptableexcipients; together with (ii) instructions how to administer saidpharmaceutical composition for the treatment of a male patient in needof increased testosterone levels, in particular for the treatment ofhypogonadism in a male patient, preferably an overweight or obese malepatient.

In a further aspect the present invention relates to a method for thetreatment of a male patient in need of increased testosterone levelscomprising administering to said patient an effective amount of4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile.

According to a further aspect of the invention there is provided amethod for the treatment of hypogonadism comprising the administrationto a male patient in need thereof an effective amount of4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile.

The dose can be from about 0.0005 mg to about 5.0 mg, preferably fromabout 0.0005 mg to about 2.0 mg and administered in a dosing regimenhaving a dosing periodicity ranging from about once daily to about onceevery 60 days.

ABBREVIATIONS

Throughout this specification, the following abbreviations will be used:

AE adverse eventANCOVA analysis of covariance modelAUC area under the concentration time curveBA bioavailabilityBE bioequivalence

BMD Bone Mineral Density BMI Body Mass Index

EOS end of study

FDA Food and Drug Administration

GCP good clinical practiceGnRH gonadotrophic hormone releasing hormoneHOMA-IR homeostatic model assessment of insulin resistance

HRQoL Health-related Quality of Life

i.v. intravenous(ly)LH luteinizing hormone

LLN Lower Limit of the Norm

LLOQ lower limit of quantificationmL millilitre(s)mm Hg millimeters of mercuryNCS not clinically significantNOAEL no-observable adverse effect levelNTEL no-toxic-effect levelo.d. or q.d. once a dayp.o. per os/by mouth/orallyPD pharmacodynamicspH negative log hydrogen ion concentrationPK pharmacokineticsSAE serious adverse event

SOP Standard Operating Procedure

TBD to be determined

ULN Upper Limit of the Norm DEFINITIONS

Throughout this specification and in the claims that follow, thefollowing terms are defined with the following meanings, unlessexplicitly stated otherwise.

As used herein, the terms “comprising” and “including” are used hereinin their open, non-limiting sense.

Where the plural form is used for compounds, salts, and the like, thisis taken to mean also a single compound, salt, or the like.

As used herein, “a,” “an,” “the,” “at least one,” and “one or more” areused interchangeably.

As used herein, the term “or” is generally employed in the sense asincluding “and/or” unless the context of the usage clearly indicatesotherwise.

Also herein, the recitations of numerical ranges by endpoints includeall numbers subsumed within that range (e.g., 1 to 5 includes 1, 1.5, 2,2.75, 3, 3.80, 4, 5, etc.).

The term “aromatase inhibitor” is defined as a compound that preventsthe formation of estrogens from their metabolic precursors by inhibitingthe enzyme aromatase.

As used herein, the term “compound” refers to4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile, alsoknown as4-[α-4-Cyanophenyl)-α-fluoro-1-(1,2,4-triazolyl)-methyl]-benzonitrile orCGP47645, first described in 1992 within EP 490 816 and U.S. Pat. No.5,637,605, the disclosure of which is hereby incorporated by referenceherein.

The compound4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile is acrystalline compound with a sharp melting endotherm at 169.5° C. Thecrystalline powder is not hygroscopic and is poorly soluble in water.

4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile(CGP47645) is a highly specific and potent aromatase inhibitor which wasshown here within to have a longer half life in humans than doesletrozole (Femara®), a marketed aromatase inhibitor to which CGP47645 isstructurally related. In vitro experiments with human placentalmicrosomal aromatase demonstrated an IC₅₀=6 nM. Oral administration ofCGP47645 to rats demonstrated a T½ of 75 hours. The exposure expressedas AUC was proportional to the administered dose. In two differentaromatase dependent experimental models, inhibition ofandrostenedione-induced uterine hypertrophy in rats and inhibition ofDMBA-induced mammary tumors in rats, the ED₅₀ was 0.003 mg/kg and 0.01mg/kg, respectively. These results suggested CGP47645 is approximately10-fold more potent than letrozole as an aromatase inhibitor.

The term “compound” shall here be understood to cover any and allisomers (e.g., enantiomers, stereoisomers, diastereomers, rotomers,tautomers) or any mixture of isomers, prodrugs, and any pharmaceuticallyacceptable addition salts of said compound, unless stated otherwise.

The term “testosterone level” in the context of the present inventionrefers to either total testosterone or free testosterone levels measuredin blood serum. In one embodiment, the term “testosterone level” refersto blood serum total testosterone. “Total testosterone” includestestosterone that is bound to sex hormone-binding globulin (SHBG) and istherefore not bioavailable and testosterone which either is free orloosely bound to other proteins (non-SHBG-bound). Free or bioavailabletestosterone levels will be calculated from the total testosterone andSHBG levels. Preferably testosterone levels are determined in themorning, between 6 am and 12 pm, as “morning testosterone levels”.Testosterone and SHBG levels can be determined using a simple bloodtests performed by a laboratory.

The term “a male patient in need of increased testosterone levels” isdefined as a male individual having serum total testosterone levelsbelow 450 ng/dL or below 12 nmol/L. In one embodiment the term “a malepatient in need of increased testosterone levels” is defined as a maleindividual having serum total testosterone levels below 400 ng/dL, orbelow 350 ng/dL, or below 10 nmol/L. In one embodiment the term “a malepatient in need of increased testosterone levels” is defined as a maleindividual having serum total testosterone levels below 300 ng/dL orbelow 8 nmol/L.

In another embodiment, the term “a male patient in need of increasedtestosterone levels” is defined as a male individual having—irrespectiveof testosterone levels-elevated serum total estradiol levels (and/orelevated total serum estrone and/or estrone sulfate and/or estriollevels). Elevated estradiol levels within the context of the presentinvention are defined as estradiol levels being above the ULN of therespective approved assay.

The term “overweight patient” as defined herein refers to a patient witha Body Mass Index (BMI) of equal or greater than 25 kg/m² and less than30 kg/m²′ calculated from their body weight and body height.

The term “obese patient” as defined herein refers to a patient with aBody Mass Index (BMI) of equal or greater than 30 kg/m², calculated fromtheir body weight and body height.

The Body mass index (BMI), a measurement which compares weight andheight, defines people as overweight (pre-obese) when their BMI isbetween 25 kg/m² and 30 kg/m², and obese when it is greater than 30kg/m².

As used herein, the term “hypogonadism” is used to refer to subjectshaving a total testosterone level of less than 400 ng/dL, in certainembodiments of less than 350 ng/dL, and in further embodiments of lessthan 300 ng/dL. Alternatively, the term “hypogonadism” is used to referto subjects having a total testosterone level of less than 12 nmol/L, incertain embodiments of less than 10 nmol/L, and in further embodimentsof less than 8 nmol/L. In one embodiment, the term “hypogonadism” isused to refer to a male individual having morning serum totaltestosterone levels below 300 ng/dL or below 8 nmol/L.

The term “hypogonadotropic patient” as defined herein refers to apatient with inappropriately low gonadotropins. In particular, a patientwith “inappropriately low gonadotropins” is defined as a patient with(i) luteinizing hormone (LH) levels ULN of the respective approvedassay, (ii) follicle stimulating hormone (FSH) levels ULN, and (iii)estradiol within or above the normal range (defined as LLN of theapproved assay).

In another embodiment, the “hypogonadotropic patient” shall have“inappropriately low gonadotropins” as defined above, and normalhypothalamic/pituitary function including (i) prolactin levels withinthe normal range, (ii) thyroid stimulating hormone (TSH) levels withinthe normal range, and (iii) ferritin levels within the normal range.

The term “hypogonadotropic hypogonadism” or “a patient withhypogonadotropic hypogonadism” as defined herein refers to a malesubject suffering from hypogonadism as defined herein, and beinghypogonadotropic as defined herein.

The term “obese, hypogonadotropic hypogonadism” or “an obese,hypogonadotropic male patient with hypogonadism” or “hypogonadotropichypogonadism in obese men” as defined herein refers to a male subjectbeing obese as defined herein, suffering from hypogonadism as definedherein, and being hypogonadotropic as defined herein. In one embodiment,such patient is defined as a subject meeting the following criteria: (a)having a Body Mass Index (BMI) ≧30 kg/m², (b) having a morning serumtotal testosterone level below 400 ng/dL, preferably below 350 ng/dL,and more preferably of below 300 ng/dL, and (c) having inappropriatelylow gonadotropins as defined herein above, and (d) having normalhypothalamic/pituitary function, as defined herein above.

The term “overweight hypogonadotropic hypogonadism” or “an overweight,hypogonadotropic male patient with hypogonadism” or “hypogonadotropichypogonadism in overweight men” as defined herein refers to a malesubject being overweight as defined herein, suffering from hypogonadismas defined herein, and being hypogonadotropic as defined herein. In oneembodiment, such patient is defined as a subject meeting the followingcriteria: (a) having a Body Mass Index (BMI) of equal or greater than 25kg/m² and less than 30 kg/m², (b) having a morning serum totaltestosterone level below 400 ng/dL, preferably below 350 ng/dL, and morepreferably of below 300 ng/dL, and (c) having inappropriately lowgonadotropins, as defined herein above, and (d) having normalhypothalamic/pituitary function, as defined herein above.

As used herein, the term “normalization of testosterone levels” isdefined as an elevation of the serum total testosterone levels,preferably the morning serum total testosterone levels, to above 300ng/dL or above 8 nmol/L. In one embodiment, it is defined as anelevation of the serum total testosterone levels, preferably the morningserum total testosterone levels, to above 350 ng/dL, to above 400 ng/dL,to above 450 ng/dL or to above 8 nmol/L.

As used herein, the term “increasing testosterone levels” is defined asincreasing the total morning serum testosterone level afteradministration of the compound according to the invention by at least10% in comparison to the testosterone level prior to administration ofthe compound. In certain embodiments, the term “increasing testosteronelevels” is defined as increasing the total morning serum testosteronelevel after the administration of a therapeutically effective amount ofthe compound to a male patient according to the invention by at least15%, at least 20%, at least 25%, at least 30%, at least 35%, at least40%, at least 45%, at least 50%, at least 55%, at least 60%, at least65%, at least 70%, or even higher, in comparison to the testosteronelevel prior to administration of the compound.

The term “treatment of hypogonadism” as defined herein refers to thetreatment of the disease hypogonadism, wherein the disease is defined asset out in the introductory part here within. In one aspect, the term“treatment of hypogonadism” comprises the treatment of patients withreduced serum testosterone levels.

As used herein, the term “a dosing regimen having a dosing periodicityranging from about once daily to about once every 60 days” refers to adosing regimen wherein the active compound could be administered onceevery 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, . . . 21, . . . ,26, 27, 28, 29, 30 . . . , 35, . . . , 42, . . . , 49, . . . , 56, 57,58, 59, 60 days. This term comprises e.g. dosing regimens having (i) adosing periodicity ranging from about once daily to about once every 60days, (ii) a dosing periodicity ranging from about once every 2 days toabout once every 40 days or 6 weeks, (iii) a dosing periodicity rangingfrom about once every 5 days to about once monthly or about once every 4weeks or about once every 30 days, (iv) a dosing periodicity rangingfrom about once weekly or about once every 7 days to about once every 3weeks or about once every 20 days, or (v) a dosing periodicity rangingfrom about once weekly or about once every 7 days to about once biweeklyor once every 10 days.

In this context the term “about” shall have the meaning from “plus/minus1 day” for a dosing regimen of once every 3 days to “plus/minus 10 days”for a dosing regimen of once every 60 days. A dosing regimen of “aboutonce every 3 days” refers to a dosing regimen of one dose administeredevery 3 days plus/minus 1 day; a dosing regimen of “about once weekly”refers to a dosing regimen of one dose administered every 7 dayplus/minus 2 days; a dosing regimen of “about once biweekly” refers to adosing regimen of one dose administered every 14 day plus/minus 3 days;a dosing regimen of “about once every 4 weeks” refers to a dosingregimen of one dose administered every 28 days plus/minus 4 days; adosing regimen of “about once monthly” refers to a dosing regimen of onedose administered every 30 days plus/minus 4 days; a dosing regimen of“about once every 5 weeks” refers to a dosing regimen of one doseadministered every 35 days plus/minus 5 days; and a dosing regimen of“about once every 6 weeks” refers to a dosing regimen of one doseadministered every 42 days plus/minus 6 days.

As used herein the term “about” in connection with a particular drugdose shall have the meaning of a drug dose in the range of plus/minus10% w/w, preferably plus/minus 5% w/w or less, of the nominal drug dose.By way of example, a nominal dose of about 0.01 mg active ingredient maycontain from 0.009 to 0.011 mg, preferably from 0.0095 to 0.0105 activeingredient per dose, whereas a nominal dose of about 0.5 mg activeingredient may contain from 4.5 to 5.5 mg, preferably from 4.75 to 5.25active ingredient per dose.

As used herein, the term “elimination half-life” of a drug refers to thetime required for the concentration of the drug in serum or plasma, todecrease by half, in vivo, for example due to degradation and/orclearance or sequestration by natural mechanisms. When determinedexperimentally by measuring drug concentration in plasma samples drawnat various and successive times after drug intake, this parameter isnamed “apparent elimination half-life”, designated T½. Methods forpharmacokinetic analysis and determination of drug half-life will befamiliar to those skilled in the art. Pharmacokinetic parameters such as“apparent elimination half-life” T½ and area under the curve (AUC) canbe determined from a curve of plasma or serum concentration of the drugagainst time. In particular, the following pharmacokinetic definitionsshall apply:

-   AUC_(0-t) the AUC from time zero to time ‘t’, where t is the last    sampling time point [mass×time×volume⁻¹].-   AUC_(0-∞) the AUC from time zero to infinity [mass×time×volume⁻¹].-   C_(max) the maximum (peak) observed plasma, blood, serum, or other    body fluid drug concentration after single dose administration    [mass×volume⁻¹].-   C_(last) The last measurable plasma, blood, serum, or other body    fluid drug concentration-   CL the total body clearance of drug from the plasma [volume×time⁻¹].    -   Clearance values from other body fluids may be noted by use of        proper subscripts, for example CL_(b) refers to clearance from        the blood and CL_(u) clearance of unbound drug from the plasma.        If the clearance is following extravascular dose and        bioavailability parameter is not known, then the notation should        be CL/F.-   t time after drug administration [time]-   T_(last) time of last measurable concentration (when C_(last)    occurs)-   T_(max) the time to reach maximum (peak) plasma, blood, serum, or    other body fluid drug concentration after single dose administration    [time].-   T_(1/2) the elimination half-life associated with the terminal slope    (λ_(z)) of a semilogarithmic concentration-time curve [time].

The drug concentration in plasma and/or serum samples can be determinedby a number of different ways, e.g. HPLC or LC-MS/MS analyses. In oneembodiment, the concentration of4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile in plasmais analyzed using a validated LC-MS/MS method with a lower limit ofquantification (LLOQ) at 0.1 ng/mL or better. In another embodiment, theconcentration of4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile in humanplasma is analyzed using a validated LC-MS/MS method with a lower limitof quantification (LLOQ) at 0.025 ng/mL.

As used herein the term “about” in connection with a particular apparentelimination half-life shall have the meaning of an apparent eliminationhalf-life in the range of plus/minus 20% w/w, preferably plus/minus 15%w/w or less, of the particularly mentioned apparent eliminationhalf-life. In one embodiment, the term “about” in connection with aparticular apparent elimination half-life shall have the meaning from“plus/minus 2 day” for an apparent elimination half-life of about 14days to “plus/minus 5 days” for an apparent elimination half-life ofabout 30 days. An apparent elimination half-life of about 20 days shallrefer to an apparent elimination half-life of 20 days “plus/minus 3days”, an apparent elimination half-life of about 25 days shall refer toan apparent elimination half-life of 25 days “plus/minus 4 days”, and anapparent elimination half-life of about 30 days shall refer to anapparent elimination half-life of 30 days “plus/minus 5 days”.

As used herein, the term “treatment period” refers to the length of thetime period wherein the compound is administered to a patient. Thephrase “a treatment period of at least about two months” shall have themeaning the compound shall be administered continuously (according tothe dosing regimen) for at least 2 months, but potentially also longer,e.g. continuously for at least 3, 4, 5, 6, 7, 8, 9, 10, 11, etc months.In general, treatment could also exceed a time period of 12 months, i.e.the compound might be considered for continuous long term treatment.However, there might be circumstances under which shorter treatmentperiods or intermittent treatment periods are advisable.

As used herein the term “about” in connection with a particular lengthof treatment period shall have the meaning of “plus/minus 5 days” forevery month of treatment, i.e. a treatment period of “about two months”shall refer to a treatment period of two months plus/minus 10 days, atreatment period of “about three months” shall refer to a treatmentperiod of three months plus/minus 15 days, etc.

DETAILED DESCRIPTION OF THE INVENTION

The aromatase inhibitor4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile is nowshown to have the potential to address specifically the needs of malepatients being in need of increased testosterone levels, in particularmale patients being overweight or obese and/or suffering fromhypogonadism, especially hypogonadotropic hypogonadism.

The aromatase enzyme catalyzes the conversion of endogenous testosteroneinto estradiol and is furthermore in particular present in excessadipose tissue. Elevated serum estradiol levels may inhibit pituitary LHsecretion and thereby reduce serum testosterone level. Administration of4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile, a highlyselective aromatase inhibitor, shows dose dependent reduction of theconversion of testosterone to estrone, estrone sulfate and estradiol,and thereby an increase of endogenous testosterone levels.

Whereas conventional medical therapies for hypogonadism work bysupplementing testosterone or administration of HCG or gonadotropins,administration of4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile inhibitstestosterone conversion by aromatase, especially local testosteroneconversion by aromatase in fat tissue, especially targeting overweightor obese patients. Since testosterone deficiency in men, in particularin men with overweight or obesity is often associated with metabolicabnormalities including insulin resistance, glucose intolerance, andlipid abnormalities, contributing to an increased incidence of metabolicsyndrome, type II diabetes and cardiovascular diseases, administrationof 4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]-bisbenzonitrile isconsidered to be especially suited for this patient population.

Accordingly, administration of4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]-bisbenzonitrile leads toimproved treatment efficacy in overweight or obese male patients withconfirmed hypogonadotropic hypogonadism via inhibition of testosteroneto estrogen conversion at all sites, especially however in the adiposetissue. Administration is considered especially useful if the patientssuffer from one or more disorders selected from insulin resistance,glucose intolerance and dyslipidaemia. Increasing testosterone levels byadministration of4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile isconsidered especially useful for improving insulin sensitivity,improving glucose metabolism and/or improving the lipid profile in thispatient population.

In particular, administration of4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]-bisbenzonitrile isconsidered to effectively improve insulin sensitivity in the overweightor obese male patient with hypogonadotropic hypogonadism by normalizingtestosterone levels. In addition, the treatment according to theinvention is thought to improve insulin sensitivity with improvedglycaemic control (as measurable by lower postprandial glucose, lowerHbA1c levels), to prevent progression of pre-diabetes to diabetes, tosupport the reduction of body fat mass and to improve body lean mass.

Furthermore, administration of4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]-bisbenzonitrile isconsidered to prevent, improve or treat other conditions associated withhypogonadism including, but is not limited to, decreased libido,decreased spontaneous erections, erectile dysfunction, decreasedfertility, loss of body hair, reduced shaving, lack of energy, fatigue,impaired cognition, depression, changes in mood, low bone mineraldensity, increased risk of fractures, decreased muscle mass, decreasedmuscle strength, increased abdominal fat mass, limited body performancecapacity and cardiovascular risks.

Administration of4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]-bisbenzonitrileaccording to the invention is also considered useful when the malepatient is in need of increased muscle mass and strength, when thepatient is in need of a normalized body composition, when the patient isin need of a decrease in abdominal fat mass (as assessed by waistcircumference and/or waist/hip circumference ratio), when the patient isin need of an improved sexual function and desire, when the patient isin need of increased fertility, and/or when the patient is in need ofincreased bone mineral density.

4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile is apotent and selective inhibitor of aromatase. The IC₅₀ and K_(i) valuesfor aromatase inhibition were determined in the microsomal fraction ofhuman placenta and showed that the compound is a competitive inhibitorwith an IC₅₀ of approximately 6.2 nM [Batzl-Hartmann et al, 1994].

Toxicologic studies of4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile in femaleand male dogs showed that there was no consistent difference in exposure(AUC and C_(max)) between male and female dogs. T_(max) values wereranging from 1 h to 24 hrs post dose. Generally, the inter-animalvariability in C_(max) levels was small. In general, following weeklyoral dosing of4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile for 4 or22 weeks, the mean plasma exposure to the compound was similar to thatobserved after a single dose at all dose levels tested, indicating thereis no drug accumulation. An increase in exposure (AUC and C_(max)) wasgenerally proportional to the dose increase for male and female dogsafter single and multiple doses of4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile at alldose levels tested. Furthermore, measurement of testosterone levels inthe serum of male dogs after 1, 4 and 12 weeks of dosing showeddramatically elevated testosterone levels at all dose levelsdemonstrating the potential of4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile.

In humans, the compound was initially studied in a single, ascendingdose protocol in human female volunteers to assess safety andtolerability (see Example 3), as well as an¹⁴C-4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile ADMEstudy (Example 4) to determine tissue half life of the drug. The firststudy showed that the median T_(max) occurred within 1 hour ofingestion, and that the half life was extremely long, approximately 25days at doses above 0.01 mg. In the human ADME study in postmenopausalwomen, the compound accumulated in fat tissue at a 1-3 fold rate incomparison to the exposure as plasma, with the same clearance pattern.Given that the excess aromatase activity in overweight or obesehypogonadotropic men with hypogonadism occurs primarily in the adiposetissue, 4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrileis considered to have the ideal pharmacokinetic distribution profile foroptimal suppression of aromatase activity. Suppression of adiposearomatase activity is assumed to result in reduction of serum estradiol,increase of LH and FSH, and increase in serum testosterone.

The ongoing study of4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile for thetreatment of obese hypogonadotropic male patients with hypogonadismshows the effectiveness of this new treatment regimen in the targetpatient population (Example 5).

An effective amount of4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile for thetreatment of overweight or obese hypogonadotropic male patients withhypogonadism is considered to be in the range from about 0.0005 mg toabout 5.0 mg, preferably from about 0.0005 mg to about 2.0 mg,preferably from about 0.001 mg to about 1.0 mg, more preferably fromabout 0.005 mg to about 0.5 mg, most preferably from about 0.01 mg toabout 0.1 mg, from about 0.005 mg to less than 0.05 mg4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile per dose.In one embodiment, the effective dose is considered to be higher than0.0005 mg, 0.001 mg, 0.005 mg, or 0.01 mg, but lower than 2.0 mg, 1.0mg, 0.5 mg, 0.1 mg, or 0.05 mg4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile per dose.In an alternative embodiment, the effective dose is considered to be inthe range from about 0.005 mg to less than 0.01 mg.

In another embodiment it might be considered to start treatment with adefined loading dose of4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile, and thento assess the testosterone response after a single dose (e.g. after 1,2, 3, 4, 5 or 6 days or even more than 6 days after a single dose), andadjust the next dose according to the treatment regimen (e.g. dailydose, weekly dose, or monthly dose) up or down based on the acutetestosterone response. In one embodiment of the invention the loadingdose of 4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitriledose is 0.3 mg followed by a weekly dose of 0.1 mg.

The present invention discloses an optimized treatment regimen providingrelief of the testosterone deficit driven symptoms of hypogonadism withadditional beneficiary treatment effects. The development of anaromatase inhibitor especially suited for hypogonadal male patientsprovides a novel treatment option for this disease. The presentinvention especially addresses overweight or obese hypogonadotropichypogonadal male patients with associated symptoms and disorders.

Accordingly, the present invention concerns the use of the compound4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile in thetreatment of a male patient in need of increased testosterone levels. Inone embodiment the present invention concerns the use of the compound4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile in thetreatment of an obese or overweight male patient.

In one embodiment the present invention concerns the use of the compound4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile in thetreatment of hypogonadism in a male patient, preferably hypogonadotropichypogonadism in a male patient, most preferably hypogonadotropichypogonadism in an overweight or obese male patient.

Furthermore, the present invention concerns the use of the compound4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile in thetreatment of a male patient in need of increased testosterone levels,wherein the compound is provided in a form comprising from about 0.0005mg to about 5.0 mg, preferably from about 0.0005 mg to about 2.0 mg4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]-bisbenzonitrile per doseand is for administration according to a dosing regimen having a dosingperiodicity ranging from about once daily to about once every 60 days.

In the context of the present invention the wording “the use of thecompound 4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrilein the treatment of ( . . . )” shall be construed either as “thecompound 4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrilefor use in the treatment of ( . . . )” or as “use of the compound4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile for themanufacture of a medicament for the treatment of ( . . . )”. Bothmeanings are equally contemplated within the scope of the invention.

In one embodiment, the patient is a male human patient, preferably anoverweight or obese male human patient. Treatment of overweight or obesemale human patients is most preferred for hypogonadism and associatedconditions; however treatment of other male patients being in need ofincreased testosterone might also be contemplated if appropriate.

In one embodiment, the male patient in need of increased testosteronelevels suffers from hypogonadism, preferably hypogonadotropichypogonadism. In particular, the present invention relates to thetreatment of hypogonadotropic hypogonadism in obese or overweight malehuman patients.

In one embodiment, the present invention relates to the use of thecompound in the above mentioned patient population for increasing,preferably normalizing testosterone levels. In particular, increasing,preferably normalizing testosterone levels in an overweight or obesemale patient with hypogonadotropic hypogonadism is considered.

A low serum testosterone concentration predicts or is associated withthe metabolic syndrome and type II diabetes, in particular in men withoverweight or obesity.

Accordingly, in one embodiment, the present invention relates to the useof the compound for the prevention or treatment of one or more disordersselected from metabolic syndrome, type II diabetes, obesity andcardiovascular disease in the above mentioned patients, preferably inpatients suffering from hypogonadism or hypogonadotropic hypogonadism,preferably in overweight or obese patients suffering from hypogonadismor hypogonadotropic hypogonadism.

In another embodiment, the present invention relates to the use of thecompound for the prevention or treatment of one or more disordersselected from insulin resistance, glucose intolerance and dyslipidaemiain the above mentioned patients, preferably in patients suffering fromhypogonadism or hypogonadotropic hypogonadism, preferably in overweightor obese patients suffering from hypogonadism or hypogonadotropichypogonadism.

In a further embodiment, the present invention relates to the use of thecompound for the improvement of insulin sensitivity and/or glucosemetabolism and/or the lipid profile in the above mentioned patients,preferably in patients suffering from hypogonadism or hypogonadotropichypogonadism, preferably in overweight or obese patients suffering fromhypogonadism or hypogonadotropic hypogonadism.

In addition, the present invention relates to the use of the compoundfor the prevention or treatment of one or more disorders selected fromthe group consisting of decreased libido, decreased spontaneouserections, erectile dysfunction, decreased fertility, loss of body hair,reduced shaving, lack of energy, fatigue, impaired cognition,depression, changes in mood, low bone mineral density, increased risk offractures, decreased muscle mass, decreased muscle strength, increasedabdominal fat mass and limited body performance capacity, wherein thepatient is in need of increased testosterone levels. In particular, thepatient has hypogonadism or hypogonadotropic hypogonadism, preferablyoverweight or obese hypogonadotropic hypogonadism.

In further embodiments of the invention relating to the use of thecompound, as herein defined, the compound is provided in a formcomprising from about 0.0005 mg to about 5.0 mg, preferably from about0.0005 mg to about 2.0 mg4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile per dose.E.g. the compound can be provided in a form comprising about 0.0005 mg,about 0.001 mg, about 0.005 mg, about 0.006 mg, about 0.007 mg, about0.008 mg, about 0.009 mg, about 0.01 mg, about 0.015 mg, about 0.02 mg,about 0.025 mg, about 0.03 mg, about 0.035 mg, about 0.04 mg, about 0.45mg, about 0.05 mg, about 0.06 mg, about 0.07 mg, about 0.08 mg, about0.09 mg, about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about0.3 mg, about 0.35 mg, about 0.4 mg, about 0.45 mg, about 0.5 mg, about0.75 mg, about 1 mg or at maximum about 2 mg or 5 mg4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile per dose.E.g. the compound can be provided in a form comprising about 0.1 mg4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile per dose.In one embodiment, the compound is provided in a form comprising about0.01 mg 4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrileper dose.

In particular, the compound is provided in a form comprising from about0.0005 mg to about 0.5 mg4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile per dose,preferably in a form comprising from about 0.001 mg to about 1.0 mg,more preferably from about 0.005 mg to about 0.5 mg, most preferablyfrom about 0.01 mg to about 0.1 mg, or from about 0.005 mg to less than0.05 mg 4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrileper dose.

In one embodiment, the compound is to be administered according to adosing regimen having a dosing periodicity ranging from one doseadministered about once daily, preferably once weekly or once biweekly,to one dose administered about once every 60 days. In one embodiment,the present invention relates to the use of the compound according to adosing regimen with a dosing periodicity of one dose administered aboutonce daily, about once every 2 days, about once every 5 days, about onceweekly, about once biweekly, about once every 3 weeks, about once every4 weeks, about once monthly and about once every 6 weeks, preferablyabout once weekly or once biweekly.

In further embodiments of the invention relating to the use of thecompound, the compound is provided in any form as set out abovecomprising from about 0.0005 mg to about 1.0 mg per dose, beingadministered according to a dosing regimen having a dosing periodicityselected from about once daily, about once every two days, about onceweekly, about once every 10 days, about once biweekly, about once every4 weeks, about once monthly and about once every 6 weeks. In particular,the compound is provided in a form comprising from about 0.01 mg toabout 0.1 mg4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile per dose,e.g. comprising about 0.01 mg, about 0.02 mg, about 0.03 mg, about 0.04mg, about 0.05 mg, about 0.06 mg, about 0.07 mg, about 0.08 mg or about0.09 mg per dose, preferably 0.1 mg per dose, being administeredaccording to a dosing regimen having a dosing periodicity of about onceweekly or once biweekly or about every 4 weeks or about once monthly.

In some embodiments, the compound is to be administered on anintermittent basis. In these embodiments the compound, e.g. a dose thatcomprises from about 0.0005 mg to about 5.0 mg, preferably from about0.0005 mg to about 2.0 mg4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile, isadministered to a patient for at least one day, optionally followed byfurther doses according to a dosing regimen as described herein above,for example in a dosing regimen having a dosing periodicity ranging fromabout once daily to about once every 60 days, followed by a period of nodosing for a period of about one day to about 6 month or longer, forexample for a period of about one day, of about two days, of about oneweek, of about 10 days, of about two weeks, of about 4 weeks, of aboutone month, of about 6 weeks, of about 2 month, of about 3 months, ofabout 4 month, of about 5 month or of about 6 month.

In one aspect of the invention, the compound4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile isprovided for oral administration.

In another aspect of the invention, the compound4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile whenadministered to the patient, shows an apparent elimination half-life ofat least about 14 days, at least about 20 days, and at least about 25days. In one embodiment, the compound may even show an apparentelimination half-life of at least about 30 days or even at least 35days. In another embodiment, the compound may show an apparentelimination half-life of approximately 22 to 29 days. In anotherembodiment, the compound may show an apparent elimination half-life ofapproximately 23 to 27 days. This extraordinary long half-life in humanswas demonstrated by way of Examples 3 and 4. The results observed werecompletely unexpected in view of the previous rat experiments showing ahalf-life of about a week [Batzl-Hartmann et al, 1994 and Bhatnagar etal, 1996]. This surprising extremely long half-life of the compound inhumans gives rise to the particular dosing scheduled of the invention.

In one embodiment of the invention, the compound4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile is to beadministered to the patient as defined herein for a treatment period ofat least about two months, preferably at least about three months. Inanother embodiment, the administration of the compound as defined hereincan extend even longer and be provided for continuous treatment.

In addition, the present invention refers to a method for the treatmentof a male patient in need of increased testosterone levels comprisingadministering to said patient an effective amount of4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile.

Furthermore, the invention relates to a method for the treatment of amale patient in need of increased testosterone levels comprisingadministering to said patient an effective amount of4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile in a dosefrom about 0.0005 mg to about 5.0 mg, preferably in a dose from about0.0005 mg to about 2.0 mg in a dosing regimen having a dosingperiodicity ranging from about once once daily to about once every 60days.

In one embodiment, said male patient is obese. In another embodimentsaid male patient is overweight. In another embodiment, the method isfor the treatment of hypogonadism or hypogonadotropic hypogonadism. Inparticular, the method of treatment is for the treatment of hypogonadismin an overweight or obese male patient, preferably for the treatment ofhypogonadotropic hypogonadism in an overweight or obese male patient.

Said male patient being in need of increased testosterone levels mayalso be in need of the prevention or treatment of one or more disordersselected from metabolic syndrome, type II diabetes, obesity andcardiovascular disease. In a further embodiment said patient is in needof the prevention or treatment of one more disorders selected frominsulin resistance, glucose intolerance and dyslipidaemia. Inparticular, the patient is in need of improved insulin sensitivity, orin need of improved glucose metabolism, or in need of an improved lipidprofile.

Said male patient being in need of increased testosterone levels mayalso be in need of the prevention or treatment of one or more disordersselected from the group consisting of decreased libido, decreasedspontaneous erections, erectile dysfunction, decreased fertility, lossof body hair, reduced shaving, lack of energy, fatigue, impairedcognition, depression, changes in mood, low bone mineral density,increased risk of fractures, decreased muscle mass, decreased musclestrength, increased abdominal fat mass and limited body performancecapacity.

In a further embodiment, said male patient being in need of increasedtestosterone levels and/or suffering from hypogonadism is in need ofincreased muscle mass and strength, in need of a normalized bodycomposition, in need of a decrease in abdominal fat mass, in need of animproved sexual function and desire, in need of increased fertility, orin need of increased bone mineral density.

Furthermore, the invention relates to a method for the treatment of amale patient in need of increased testosterone levels comprisingadministering to said patient an effective amount of4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile, whereinthe administration of the compound increases the testosterone level byat least 10% over the testosterone level prior to administration of thecompound. In a further embodiment, administration of the compoundnormalizes testosterone levels.

All embodiments set out above for the use of the compound4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile for thetreatment of one of the aforementioned diseases shall apply mutatismutandis for the above mentioned method of treatments of the respectivediseases with this compound.

Accordingly, an effective amount of4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile can befrom about 0.0005 mg to about 5.0 mg per dose, from about 0.0005 mg toabout 2.0 mg per dose, from about 0.001 mg to about 1.0 mg per dose, orfrom about 0.005 mg to about 0.5 mg per dose, e.g. 0.001 mg, about 0.005mg, about 0.006 mg, about 0.007 mg, about 0.008 mg, about 0.009 mg,about 0.01 mg, about 0.015 mg, about 0.02 mg, about 0.025 mg, about 0.03mg, about 0.035 mg, about 0.04 mg, about 0.45 mg, about 0.05 mg, about0.06 mg, about 0.07 mg, about 0.08 mg, about 0.09 mg, about 0.1 mg,about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.35 mg,about 0.4 mg, about 0.45 mg, about 0.5 mg per dose. In particular, aneffective amount of4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]-bisbenzonitrile is about0.01 mg per dose.

An effective amount of4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile selectedfrom about 0.0005 mg to about 5.0 mg per dose, preferably from about0.0005 mg to about 2.0 mg per dose can be administered according to adosing regimen having a dosing periodicity ranging from about once dailyto about once every 60 days or ranging from about once weekly to aboutonce monthly.

More specifically, an effective amount of4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile fromabout 0.0005 mg to about 5.0 mg per dose, preferably from about 0.0005mg to about 2.0 mg per dose, more preferably from about 0.01 mg to about0.1 mg per dose can be administered according to a dosing regimen havinga dosing periodicity selected from about once daily, once every twodays, once weekly, about once every 10 days, about once biweekly, aboutonce every 4 weeks, about once monthly and about once every 6 weeks. Aneffective amount of4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile fromabout 0.01 mg to about 0.1 mg per dose (e.g. about 0.01 mg, about 0.02mg, about 0.03 mg, about 0.04 mg, about 0.05 mg, about 0.06 mg, about0.07 mg, about 0.08 mg or about 0.09 mg per dose) can be administeredaccording to a dosing regimen having a dosing periodicity of about onceweekly or once biweekly or once every 4 weeks or once monthly.

In another embodiment, the compound shows when administered according tothe treatment method of the invention an apparent elimination half-lifeof at least about 14 days, preferably of at least about 20 days, morepreferably of at least about 25 days, and most preferably of at leastabout 30 days.

In a further embodiment, the invention relates to a method for thetreatment of a male patient in need of increased testosterone levels asdefined herewithin comprising administering to said patient a singledose of 4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile,wherein said dose results in an increased effective blood concentrationof testosterone over a period of time from 3 to 30 days. In particular,the serum concentration of testosterone is increased by at least 10%over the serum testosterone concentration prior to administration of thecompound.

The compound4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile may beprovided in various formulations such as parentally (e.g. aqueous oroily suspensions) or orally (e.g., tablets, powders, capsules, granules,aqueous or oily suspensions). Preferably, the compound is provided in anorally available formulation to be administered according to thedescribed dosing regimen. However, slow release formulation or depot ortransdermal formulations could also be used to administer the compound.

Thus, according to a further embodiment of the invention, there isprovided an oral pharmaceutical formulation comprising from about 0.0005mg to about 5.0 mg, preferably from about 0.0005 mg to about 2.0 mg4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile per dose,optionally in combination with one or more pharmaceutically acceptableexcipients.

In one embodiment, the pharmaceutical composition comprises from about0.001 mg to about 1.0 mg, preferably from about 0.005 mg to about 0.5mg, more preferably from about 0.01 mg to about 0.1 mg, e.g. about 0.02mg, about 0.03 mg, about 0.04 mg, about 0.05 mg, about 0.06 mg, about0.07 mg, about 0.08 mg, or about 0.09 mg, most preferably about 0.01 mg4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile per dose.

For preparing pharmaceutical formulations of the invention, inert,pharmaceutically acceptable excipients can be added to the components ofthe composition which can either be solid or liquid. Solid formpreparations comprise powders, tablets, dispersible granules, capsulesand cachets.

A solid pharmaceutically acceptable excipient can be one or moresubstances which may act as carriers, diluents, flavoring agents,solubilizers, lubricants, suspending agents, binders, and/or tabletdisintegrating agents; it can also be an encapsulating material.

In powders, a finely divided solid excipient is provided in a mixturewith the finely divided active component. In tablets, the activecomponent is mixed with an excipient having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired.

Suitable excipients include magnesium carbonate, magnesium stearate,talc, lactose, lactose monohydrate, sugar, pectin, dextrin, starch,tragacanth, microcrystalline cellulose, methyl cellulose, sodiumcarboxymethyl cellulose, corn starch, colloidal anhydrous Silica,titanium dioxide, a low-melting wax, cocoa butter, and the like.

The term formulation is intended to include the mixture of the activecomponent(s) with encapsulating material as a carrier providing acapsule in which the active compound (with or without other carriers) issurrounded by a carrier which is thus in association with it. Similarly,cachets are included. Tablets, powders, cachets, and capsules can beused as solid dosage forms suitable for oral administration.

Liquid form compositions include solutions, suspensions, and emulsions.Sterile water or water-propylene glycol solutions of the activecompounds may be mentioned as an example of liquid preparations suitablefor parenteral administration. Liquid compositions can also beformulated in solution in aqueous polyethylene glycol solution. Aqueoussolutions for oral administration can be prepared by dissolving theactive component in water and adding suitable colorants, flavoringagents, stabilizers, and thickening agents as desired. Aqueoussuspensions for oral use can be made by dispersing the finely dividedactive component in water together with a viscous material such asnatural synthetic gums, resins, methyl cellulose, sodium carboxymethylcellulose, and other suspending agents known to the pharmaceuticalformulation art.

The pharmaceutical formulation can be in unit dosage form. In such form,the composition is divided into unit doses containing appropriatequantities of the active component(s). The unit dosage form can be apackaged preparation, the package containing discrete quantities of thepreparations, for example, packeted tablets, capsules, and powders invials or ampoules. The unit dosage form can also be a capsule, cachet,or tablet itself, or it can be the appropriate number of any of thesepackaged forms.

In a further embodiment, the invention pertains to an oralpharmaceutical composition as set out above which shows, whenadministered to the patient, an apparent elimination half-life of4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile of atleast about 14 days, preferably of at least about 20 days, morepreferably of at least about 25 days and most preferably of at leastabout 30 days. In one embodiment, the compound may even show an apparentelimination half-life of at least about 30 days. In another embodiment,the compound may show an apparent elimination half-life of approximately22 to 29 days.

In another embodiment, the invention refers to a kit of partscomprising: (i) a pharmaceutical composition comprising the compound4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile asdefined herewithin; together with (ii) instructions how to administersaid pharmaceutical composition for the treatment of a male patient inneed of increased testosterone levels, in particular for the treatmentof hypogonadism or hypogonadotropic hypogonadism in a male patient,preferably an overweight or obese male patient. These instructions willexplain in detail the dosing regimen how the compound is to beadministered, as set out in more detail below.

In a further embodiment, the invention refers to a kit of partscomprising: (i) a pharmaceutical composition comprising from about0.0005 mg to about 5.0 mg, preferably from about 0.0005 mg to about 2.0mg, preferably from about 0.001 mg to about 1.0 mg, more preferably fromabout 0.005 mg to about 0.5 mg, most preferably from about 0.01 mg toabout 0.1 mg, or from about 0.005 mg to less than 0.01 mg4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile per dose;together with (ii) instructions how to administer said pharmaceuticalcomposition. These instructions will explain in detail the dosingregimen how the compound is to be administered, as set out in moredetail below.

In a further embodiment, the kits of parts as defined here withincomprise instructions stating that pharmaceutical composition is for thetreatment of a male patient in need of increased testosterone levels, inparticular for the treatment of hypogonadism or hypogonadotropichypogonadism in a male patient, preferably an overweight or obese malepatient. In particular, the instructions state that the pharmaceuticalcomposition is to be administered according to a dosing regimen having adosing periodicity ranging from about once daily to about once every 60days, preferably selected from a dosing regimen having a dosingperiodicity of about once every 2 days, about once every 5 days, aboutonce weekly, about once biweekly, about once every 3 weeks, about onceevery 4 weeks, about once monthly and about once every 6 weeks,preferably about once weekly or once biweekly.

In another embodiment, the instructions of the kits of parts areprovided either as a leaflet or in the form of a printed matter on thepackaging of the pharmaceutical composition.

This invention is further illustrated by the following examples whichshould not be construed as limiting.

EXAMPLES Example 1 Preparation of4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile

The following example describes a method for the synthesis of4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile (alsoknown as4-[α-4-Cyanophenyl)-α-fluoro-1-1,2,4-triazolyl)-methyl]-benzonitrile orCGP47645) as disclosed within Lang et al., U.S. Pat. No. 5,637,605:

A solution of 0.8 mmol of potassium hexamethyldisilazane in 1.6 ml oftoluene is diluted with 5 ml of THF and, after cooling to −78° C., asolution of 190 mg of4-[α-(4-cyanophenyl)-1-(1,2,4-triazolyl)methyl]-benzonitrile (seeEP-A-236 940, Ex. 20a) in 3 ml of

THF is added thereto. After stirring for 1 hour at the same temperature,there are added dropwise to the dark-red solution 301 mg ofN-fluoro-dimethylsaccharinsultam in 3 ml of THF. After a further 1.5hours at −78° C., the reaction mixture is heated to room temperaturewithin 1 hour and poured onto a saturated solution of ammonium chloridein water and then extracted with methylene chloride. Drying overmagnesium chloride and concentration of the solvent by evaporationyields the crude product which is purified by means offlash-chromatography (SiO₂, hexane/ethyl acetate 9:1, 4:1 to 1:1). TLC(SiO₂, CHCl₃/methanol 9:1, Rf=0.85); IR (KBr): 2220 cm⁻¹; ¹H-NMR(CDCl₃): δ (ppm)=7.46 and 7.76 (8H, m), 8.07 (1H, s), 8.16 (1H, s).

All disclosure relevant to the preparation of4-[α-4-Cyanophenyl)-α-fluoro-1-1,2,4-triazolyl)-methyl]-benzonitriledescribed in Lang et al., U.S. Pat. No. 5,376,669 is hereby incorporatedby reference herein.

The above paragraph refers to EP-A-236 940, Ex. 20a. The U.S. equivalentto EP-236 940 is Bowman, U.S. Pat. No. 4,749,713. Example 20 (a) ofEP-A-236 940 (U.S. Pat. No. 4,749,713) states that4-[1-(1,2,4-Triazolyl)-methyl]-benzonitrile is reacted with potassiumtert-butoxide and 4-fluorobenzonitrile according to the procedure inExample 2 of U.S. Pat. No. 4,749,713 to yield4-[α-(4-cyanophenyl)-1-(1,2,4-triazolyl)-methyl]benzonitrile, m.p. 181°C.-183° C.

The procedure of Example 2 of U.S. Pat. No. 4,749,713 provides that: Asuspension of potassium tert-butoxide (61.6 g) in dimethylformamide (500mL) is stirred and cooled to −10° C. (ice-salt bath), and a solution of4-(1-imidazolylmethyl)-benzonitrile (45.6 g) in dimethylformamide (250mL) is added so that the reaction temperature remains below 0° C. Theresulting solution is stirred at 0° C. for 0.5 hour and then a solutionof 4-fluorobenzonitrile (38.3 g) in dimethylformamide (100 mL) is addedwhile keeping reaction temperature below 5° C. After 0.75 hour, thereaction mixture is neutralized to pH 7 by addition of sufficient 3Nhydrochloric acid and the bulk of the solvents are then removed underreduced pressure. The residue is diluted with water (500 mL) and thecrude product is extracted into ethyl acetate (3×200 mL). The combinedextracts are then extracted with 3N hydrochloric acid (3×150 mL) and,after washing the latter acid extracts with ethyl acetate (100 mL), thesolution is made basic (pH 8) with 6N ammonium hydroxide and the productis again extracted into ethyl acetate (3×150 mL). The combined extractsare dried (MgSO₄), decolorized by treatment with charcoal, and thenevaporated to give crude4-[α-(4-cyanophenyl)-1-imidazolylmethyl]-benzonitrile as an oil. Thismaterial is dissolved in isopropanol (250 mL) and the warm solution isstirred with succinic acid (14.4 g). Upon dilution with diethyl ether(100 mL) and stirring at ambient temperature, the hemisuccinate saltseparates. The salt is filtered off, washed with a little coldisopropanol and then air dried to afford4-[α-(4-cyanophenyl)-1-imidazolylmethyl]-benzonitrile hemisuccinate,m.p. 149° C.-150° C. The hemifumarate salt has m.p. 157° C.-158° C.

All disclosure relevant to the preparation of4-[α-(4-cyanophenyl)-1-(1,2,4-triazolyl)-methyl]benzonitrile describedin Bowman, U.S. Pat. No. 4,749,713 is hereby incorporated by referenceherein.

Example 2 Formulations of4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile(CGP47645)

4,4′-[Fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile(CGP47645) is provided in the form of hard gelatine capsulesrepresenting an immediate release dosage form for oral administration.The dosage form is a hard gelatine capsule containing a white toyellowish powder in a pink opaque capsule, size 1 or 3. Three strengthsare provided, containing 0.1 mg, 0.5 mg or 1.0 mg CGP47645 per hardgelatine capsule. The excipients used to prepare the hard gelatinecapsules are lactose, microcrystalline cellulose, corn (maize) starch,sodium starch glycolate, magnesium stearate, colloidal silicon dioxide.All the excipients comply with the requirements of the applicablecompendial monographs (Ph.Eur., NF). The hard gelatine capsules arepackaged in HDPE bottles with aluminum induction seal equipped withchild-resistant screw-cap closures.

CGP47645 containing hard gelatine capsules are prepared by the followingprocess: The required excipients, in the respective amounts to yield thefinal composition as indicated in Table 2 below, and the appropriateamount of CGP47645 drug substance are weighed. Then, approximately 50%of corn starch is filled into suitable container, the drug substance isadded, followed by the remaining 50% of corn starch to get a sandwich ofdrug substance between two layers of maize starch. Blending and sievingthis mixture yields the drug substance (DS) premix. The remainingexcipients (microcrystalline cellulose, spray-dried lactose, sodiumstarch glycolate, and colloidal silicon dioxide [Aerosil® 200]) aremixed and sieved and transfer into a suitable container. Then the DSpremix is added into container containing the sieved excipients and themixture is blended together. Finally, pre-sieved Magnesium stearate isadded to the blend containing the DS and this mixture is blended againto yield the final blend. The final blend is filled into hard gelatincapsules.

The following Table 2 indicates the composition of the CGP47645 hardgelatin capsule of 0.1 mg, 0.5, 1 mg and 10 mg strength.

TABLE 2 Amount per capsule (mg) Ingredient 0.1 mg¹ 0.1 mg² 0.5 mg¹ 1 mg²10 mg² Capsule content CGP47645 0.1 0.1 0.5 1.0 10.0 Lactose monohydrate96.0 192.0 96.0 192.0 175.5 Cellulose, 30.0 60.0 30.0 60.0 50.0microcrystalline Corn Starch 14.15 28.4 13.75 27.5 40.0 Sodium starch7.5 15.0 7.5 15.0 15.0 glycolate (Type A) Magnesium Stearate 1.5 3.0 1.53.0 3.0 Silica, colloidal 0.75 1.5 0.75 1.5 1.5 anhydrous Capsule fillweight 150.0 300.0 150 300.0 295.0 Empty capsule shell Capsule shell48.0 76.0 48.0 76.0 76.0 Total capsule weight 198.0 376.0 198.0 376.0371.0 ¹Filled in size 3 capsules; ²Filled in size 1 capsules

Example 3 Single ascending dose study of4,4′-[Fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile(CGP47645)

This was a randomized, double-blind, placebo- and active-controlledsingle ascending dose study in pre- and post-menopausal women to assessthe safety and tolerability, PK and PD effects of single doses of4,4′-[Fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile(CGP47645). There were 8 cohorts of 8 post-menopausal subjectsrandomized 6:2, CGP47645:placebo, who received single doses of CGP47645beginning at the dose of 0.01 mg and carried through 20 mg, whichreached the limit of the toxicology exposure coverage. Patients receivedeither 0.1 mg, 1 mg, and 10 mg drug substance containing hard gelatincapsules or appropriate matching placebo capsules. For the lowest twodosing cohorts, 0.1 mg drug containing capsules were used forreconstituting the CGP47645 oral solutions for dosing the 0.01 and 0.03dosing strength (Cohort 1 and 2).

A minimal toxic dose (MTD) was not reached. A single cohort of 8pre-menopausal subjects without childbearing potential (Cohort No. 9)received CGP47645 0.1 mg or placebo, randomized 6:2, and one last cohortreceived letrozole 2.5 mg as an internal positive control cohort for thePD measurements. Table 3 presents the PK parameters based on preliminaryanalysis of the concentration-time profile obtained from this study.

TABLE 3 CGP47645 Pharmacokinetics in Post- & Pre-menopausal women AUC(0-t_(last)) C_(max) (ng/mL) T_(max) (ng*hr/mL) T_(1/2) (days) Cohort CV(hr) CV CV Dose (mg) No. Size Mean (%) Median Mean (%) Mean (%) 0.01 1(n = 5) 0.2 21.7 1 1.4 53.2 2.3 127.5 0.03 2 (n = 6) 0.4 18.7 0.6 24.134.0 16.5 36.0 0.1 3 (n = 6) 1.8 13.4 1 123.1 10.7 18.2 10.9 0.3 4 (n =6) 5.1 14.1 1 605.1 49.0 23.5 19.9 1 5 (n = 5) 12.8 22.0 1 3201.9 37.222.4 38.5 3 6 (n = 6) 38.4 17.0 1 10053.0 16.7 25.0 8.4 10 7 (n = 6)123.8 26.4 2 41745.5 17.3 27.3 17.6 20 8 (n = 6) 269.8 30.9 2 76731.611.4 26.9 16.5 0.1 9 (n = 6) 1.7 15.1 1 116.2 17.1 23.5 31.0 2.5Letrozole (n = 8) 33.5 27.0 1 1667.7 40.8 2.9 40.7

CGP47645 exhibited dose proportional pharmacokinetics and adose-dependent inhibition of estrone, estrone sulfate and estradiol. Nodifferences in CGP47645 pharmacokinetics were observed between post- andpre-menopausal women. CGP47645 is rapidly absorbed with a T_(max) of0.5-2 hrs; the median T_(max) occurred within 1 hour of ingestion. BothC_(max) & AUC increased in a dose-proportional manner. CGP47645exhibited low inter-subject variability of 10-30% and completelyunexpected long half-life in the range of 23 to 27 days.

In postmenopausal women the study showed evidence of efficacy in PDparameters with estrone suppression at least equal to letrozole alreadyat doses of 0.1 mg and 0.3 mg. In postmenopausal women, the lowestsingle dose at which transient estrogen suppression was seen was 0.01mg; and the lowest single dose at which maximal estrogen suppression wasobserved in post-menopausal women, using chemiluminescence orradioimmunoassay, was 0.1 mg. No inhibition of other enzymes involved insteroid hormone synthesis or metabolism was observed; in particularthere were no changes in androgen levels, progesterone, aldosterone,cortisol, ACTH, or 17-keto or 17-OH steroids in 24 hour urinecollections. A final review of the individual listing for bone densityand T-scores determined by DEXA indicated there were no notable changesin bone density over time for subjects in the CGP47645 cohorts thatreceived a dose of 3 mg or less, or within the letrozole 2.5 mg cohort.For subjects in the 10 mg and 20 mg dose cohorts, there was a small butclinically significant decrease in bone density at the lumbar spine, butnot at the hip, at 6 months compared to baseline.

Example 4 Pharmacokinetics of a single oral dose of 1 mg¹⁴C-4,4′-[Fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile inhealthy postmenopausal women—ADME study

The study was a single dose, single group, open label ADME study of 8healthy postmenopausal women. Subjects enrolled in the study received 1mg CGP47645 labeled with 10 μCi of 14C-CGP47645. The drug dose of 1 mgCGP47645 was selected as being presumably therapeutically relevant basedon the animal ADME information and dosage information available forother aromatase inhibitors. The study design consisted of a 28-dayscreening period, one baseline visit (Day −1), a domiciled periodbeginning from admission on Day −1 through discharge on Day 7, 2outpatient visits for PK blood collection on Days 14 (±1) and 21 (±1), 2subject specific adipose tissue collection visits, and an end-of-study 6month safety follow-up visit.

The primary goal of this study was to assess the partitioning ofCGP47645 into abdominal adipose tissue as a measure of peripheral tissuetargeting and to assess whether there may be a longer T½ metabolite, aswell as to elucidate the metabolic profile, obtain information on routesof excretion and mass balance. Adipose tissue samples were collected ina sparse sampling protocol, where each subject underwent two collectionsof adipose tissue, with each subject biopsied at different times.

The single oral administration of 1 mg ¹⁴C-CGP47645 was found to be safeand well tolerated. Following single oral administration of 1 mg¹⁴C-CGP47645 to healthy postmenopausal women, pharmacokinetics ofCGP47645 can be characterized by fast and almost complete absorptionfollowed by rapid decline in plasma concentrations suggesting extensivedistribution into the tissues. This was followed by a prolonged terminalphase with low but persistent plasma concentrations lasting longer than4000 hrs post-dose. The terminal elimination half-life was estimated tobe approximately 28 days. Concentration time profiles suggest fastequilibration of CGP47645 between tissue and blood followed by slowelimination of CGP47645 from blood which is the rate limiting step forthe CGP47645 clearance. This is reflected by parallel terminal slopes inplasma and adipose tissue, i.e. the elimination rates in plasma andtissue are similar.

Approximately 84% of the total radioactivity excreted after 6 days wasrenally eliminated of which only 16% was recovered as unchanged drug. Nometabolites were detected in plasma and ¹⁴C-CGP47645 was the onlyradioactive compound detected in all analyzed plasma samples.Concentration-time profiles in plasma of ¹⁴C-CGP47645 measured by liquidscintillation counting [LSC] and parent CGP47645 measured by liquidchromatography-mass spectroscopy [LC-MS] were almost super imposablefurther suggesting absence of metabolite(s) in plasma. However, majormechanism of ¹⁴C-CGP47645 elimination appears to be metabolism followedby renal excretion. Three main metabolites identified in urine were acarbinol derivative and two glucuronides of CGP47645. Metabolitepatterns were comparable for urine samples from different time pointssuggesting that formation of metabolites was the rate limiting step.

Overall, pharmacokinetics of ¹⁴C-CGP47645 can be characterized by fastabsorption followed by rapid decline in plasma concentrations suggestingextensive distribution into the tissues. The terminal eliminationhalf-life of the parent drug was estimated to be approximately 28 days.

Example 5 Study to analyse whether oral4,4′-[Fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile increasesor normalizes testosterone levels in obese hypogonadotropic hypogonadalmen

This is an open-label dose finding study followed by a parallel group,randomized, double-blind study to evaluate the safety, tolerability andpharmacodynamics of 12 week treatment with4,4′-[Fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile(CGP47645) in obese, hypogonadotropic hypogonadal men. The study isdesigned as a 2-part study, with Part 1 being open-label to bestdetermine the appropriate dose levels to use in Part 2, which has arandomized, double-blind, placebo controlled design. The study assessesthe safety and tolerability of CGP47645, and determines whether a lowdose of CGP47645 given at a weekly dosing interval normalizestestosterone levels and improves insulin sensitivity in obese,hypogonadotropic hypogonadal (OHH) men when compared with placebo.

Study Design:

As set out above, this is a two-part study in obese, hypogonadotropichypogonadal (OHH) men, wherein Part 1 is a single group, open label,non-randomized study establishing appropriate dosing. After all subjectshave successfully completed 4 weeks of treatment, they continue for upto a total of 12 weeks of treatment. Then Part 2 follows as a parallelgroup, randomized, double-blind, placebo-controlled design, for 12 weeksof treatment, with an interim analysis after 4 weeks of treatment. BothParts of the study have up to a 28 day screening period, a singlebaseline day, a 12 week treatment period (11 weekly doses), followed bya 3 month follow-up period.

The Screening Period is used to assess eligibility and to taper patientsoff disallowed medications. Subjects who meet the inclusion/exclusioncriteria at Screening are admitted to Baseline evaluations. Subjects areadmitted to the study site the night prior to Oral Glucose ToleranceTest (OGTT) evaluations to ensure fasting conditions are maintained. Thesame overnight domiciling applies for all scheduled OGTT evaluationdays. Following the first dose, pharmacokinetic (PK), pharmacodynamic(PD), and safety assessments are collected for up to 24 hours. Subjectsreturn to the site 1-2 days prior to each of the next 10 dosing visitsfor pharmacodynamic blood evaluations in Part 1, and up to 72 hoursprior to each dosing visit in Part 2. At the conclusion of the 12 weektreatment period, patients are asked to return to the site approximatelyonce every 6 weeks for 3 months for safety follow-up evaluations. Safetyassessments include physical examinations, ECGs, vital signs, standardclinical laboratory evaluations (hematology, blood chemistry andurinalysis), adverse event and serious adverse event monitoring. PK andPD (sex steroid) assessments take place on multiple occasions throughoutthe duration of the study, and are collected at the same time wheneverboth are scheduled on the same visit.

The 0.01 mg dose of CGP47645 administered once weekly was chosen asstarting dose on the basis of the extremely long half-life of CGP47645of approximately 22-29 days in serum and potentially even longer inadipose tissue, its linear PK profile, minimal inter patientvariability. Pharmacokinetic modeling was used to define the impact ofdose frequency and dose on steady state exposure. Once weekly dosing wasselected as the optimal approach for initial evaluation. The model wasused to estimate the dose of CGP47645 required to normalize testosteronein OHH men, and the potential impact of a loading dose. Pharmacodynamicpredictions are also based on the minimal dose (0.01 mg) in womendemonstrated to have pharmacodynamic effects in the single ascendingdose study (Example 3).

Thus, for Part 1 of the study, it was decided to start with 0.01 mg asthe loading dose, assess the testosterone response at 5 or 6 days aftera single dose, and adjust the next weekly dose up or down based on theacute testosterone response. The weekly maintenance dose is not expectedto exceed 0.5 mg. For at least the first 4 weeks of treatment, subject'ssex steroid levels are measured prior to their subsequent dosing. Thesubsequent dose is the adjusted based on the prior response.

For Part 2, the blinded study, dose adjustment based on clinicaldiscussions and/or an algorithm for both CGP47645 and placebo (based onfindings in Part 1). A fixed dose regimen consisting of a starting doseof 0.3 mg followed by a 0.1 mg weekly dosing was selected for Part 2 ofthe study.

For Part 1, the dose range finding part of the trial, if testosteronelevels are in the normal range, ⅕ of the loading dose of CGP47645 (0.002mg) or placebo will be administered in Week 2. If free testosterone isabove normal, the Week 2 dose will be 1/10 (0.001 mg) of the loadingdose. If free testosterone is below normal, the Week 2 dose will be ½ ofthe loading dose (0.005 mg). Subsequent weekly doses are adjusted on a ½log order to achieve normalization of free testosterone levels.

Study Drug:

1 mg (size 1) and 0.1 mg (size 3) capsules of CGP47645 for oral intakeas depicted in Example 2; lower doses for this study will be diluted insolution.

Population:

A total of approximately 44 subjects will be randomized to participatein the study. The subjects are adult male patients meeting the criteriaof obese, hypogonadotropic hypogonadism (OHH) who have passed screeningassessments, comply with inclusion/exclusion criteria and have providedwritten consent. For Part 1, about 14 patients are required, whereasPart 2 required up to 30 patients, randomized to active and placebotreatment in a 1:1 ratio.

Inclusion criteria comprise:

-   1. Males who meet the criteria of obese, hypogonadotropic    hypogonadism defined as:    -   a. Patients with a Body Mass Index (BMI) 30 kg/m²    -   b. Patients with a morning serum total testosterone level <300        ng/dL on at least two separate occasions during the Screening        and/or Baseline periods    -   c. Patients with inappropriately low gonadotropins at screening        given the low testosterone:        -   i. Luteinizing hormone (LH) ULN        -   ii. Follicle stimulating hormone (FSH) ULN        -   iii. Estradiol within or above the normal range (defined as            LLN of the approved assay)    -   d. Normal hypothalamic/pituitary function, including:        -   i. Prolactin: within the normal range        -   ii. Thyroid stimulating hormone (TSH): within the normal            range        -   iii. Ferritin: within the normal range-   2. Patients agree to use a barrier method of contraception (e.g.,    condom), for the duration of the study and for at least 3 months    following their Study Completion visit to prevent compound exposure    to their partners.

Exclusion criteria comprise patients with hypogonadism, not related toobesity or as a result of other underlying issues; and patients withsignificant major organ class illness (e.g. kidney or liver disease).

The primary objective of this study is to demonstrate that weeklyadministration of low doses of CGP47645 normalize testosterone levels inobese, hypogonadotropic hypogonadal (OHH) men. Furthermore, thepharmacodynamic effect of CGP47645 on insulin sensitivity (based onHOMA-IR) in OHH men is to be demonstrated.

Secondary objectives of this study include the assessment of the safetyand tolerability of CGP47645 in OHH men, assessment of thepharmacodynamic effect of CGP47645 on glucose, insulin and lipidmetabolism, and body composition in OHH men, and the determination ofthe pharmacokinetics of CGP47645 in OHH men.

Assessments and evaluations: The following assessments will be performedduring the study:

-   -   1. Background, demographic and administrative assessments        -   Inclusion/exclusion criteria; Relevant medical            history/Current medical conditions        -   Demography        -   Physical examination, including digital prostate examination        -   International Prostate Symptom Score (IPSS)        -   Hepatitis screen, HIV screen        -   Alcohol test, Drug screen        -   Prolactin, ferritin and thyroid stimulating hormone (TSH)        -   Drug administration: each time study drug is administered        -   Study Completion information        -   Comments    -   2. Safety and tolerability assessments        -   Vital signs and body measurements            -   Body height (BMI will be calculated)            -   Body weight*            -   Body temperature            -   Blood pressure, pulse rate        -   ECG evaluations        -   Hematology; Blood chemistry; Urinalysis        -   Prostate specific antigen (PSA)        -   Adverse events: from time of first administration of study            drug until Study Completion. Adverse events occurring before            starting study treatment but after signing the informed            consent form are recorded on the Medical History/Current            Medical Conditions Case Report Form.        -   Serious adverse events: from time of consent until 30 days            after Study Completion        -   Concomitant medications/Significant non-drug therapies:            Refer to entry criteria and Concomitant medication for            details of recording requirements for allowed and restricted            medications during the study.    -   3. Pharmacokinetic (PK) blood assessments: PK samples will be        collected on multiple occasions during the treatment phase of        the study. PK assessments will also be collected every 6 weeks        during the safety follow-up period. It is anticipated that the        final PK draw will take place at Week 24/EOS, with the        possibility of additional samples being collected if there is        still clinically relevant detectable blood CGP47645 levels after        that time.    -   4. Pharmacodynamic assessments (to be collected at the same time        of day on each collection day)        -   Sex hormones:            -   Testosterone (total)            -   Estradiol (total)            -   Sex hormone binding globulin (SHBG)            -   Bioavailable testosterone            -   Dihydrotestosterone (DHT)            -   Note: Free testosterone and free estradiol will be                calculated from the total testosterone/estradiol and                SHBG levels        -   Luteinizing hormone (LH), follicle stimulating hormone (FSH)            and inhibins A and B        -   Semen analysis for sperm count and motility, only if study            is open to non-vasectomized males        -   Body composition (by DEXA)        -   Body measurements            -   Body weight (derived BMI)            -   Waist circumference, hip circumference (derived                waist-hip ratio)        -   OGTT: Blood sampling at −10 minutes pre-glucose, 0            (pre-glucose), 15, 30, 60, 90, 120 and 180 minutes            post-glucose load.            -   Glucose            -   Insulin            -   HOMA-IR and QUICKI (derived from fasting insulin and                glucose values)            -   HbA1c (will be part of safety lab collection)        -   Fasting lipid parameters (LDL, HDL, triglycerides)        -   Bone biomarkers: C-terminal telopeptide (CTx1), osteocalcin,            bone alkaline phosphatase and procollagen type 1            N-propeptide (PINP)        -   Muscle function assessment by power stair climb        -   Quality of life questionnaire: Aging Males' Symptom (AMS)            Scale

Analysis Methods—Efficacy and Pharmacodynamic Analyses:

Part 1 is designed as an open label dose finding phase. The primaryefficacy endpoint at the end of Week 4 in Part 1 is the demonstrationthat total and free testosterone and estradiol can be normalized in thesubjects who have received an appropriate dose.

The primary objective of Part 2 of the study is to assess the impact ofnormalizing testosterone with CGP47645 on insulin sensitivity. The dataof the primary efficacy/pharmacodynamic variable, HOMA-IR, istransformed into log scale, for both baseline and on-treatment values,and analyzed using analysis of covariance at each time point withtreatment as a classification variable and baseline as a covariate.Point estimates and 95% confidence intervals of the treatmentdifferences are derived from the analysis of covariance. The relatedinsulin sensitivity index, QUICKI, is analyzed similarly. Thecorrelation between changes in testosterone level and changes in HOMA-IRvalues or in QUICKI values is assessed.

The secondary efficacy/pharmacodynamic variables, including sex hormonelevels, fasting and postprandial glucose (AUC and peak), postprandialinsulin, HbA1c, fasting lipids, body weight, waist-to-hip ratio,Luteinizing hormone (LH), follicle stimulating hormone (FSH), inhibin Aand B, and muscle function assessment by stair climb power, is similarlyanalyzed. Log-transformation of the data may be performed asappropriate. For data distributions requiring a nonparametric approachfor analysis, Wilcoxon rank sum test is used.

Data on bone biomarkers—C-terminal telopeptide (CTx1), osteocalcin, bonealkaline phosphatase and procollagen type 1 N-propeptide (PINP) as wellas data on semen analysis and quality of life questionnaires aresummarized by descriptive statistics.

Preliminary results of the initial 12 week treatment, open labeldose-finding portion of the study: 14 obese, hypogonadal men receivedweekly oral doses of CGP47645 from 0.003 mg to 5 mg. For example,patients received weekly oral doses of 0.1 mg per dose; of 0.3 mg perdose; of between 0.01 mg and 0.03 mg per dose; of between 0.003 mg and0.3 mg per dose; of between 0.003 mg and 1 mg per dose; of between 0.1mg and 0.3 mg per dose; of between 0.01 mg and 1 mg per dose; of between0.2 mg and 1 mg per dose; of between 0.3 mg and 1 mg per dose; ofbetween 0.1 mg and 3 mg per dose; or of between 1 mg and 5 mg per dose.Doses were adjusted to normalize testosterone, and if cumulativeexposures approached the highest single dose exposures tested (20 mg) inpostmenopausal women then dosing was stopped during the 12 weeks. Allsubjects tolerated CGP47645 well without frequent AEs, no SAEs and nowithdrawals. Preliminary analysis reveals that testosterone (measured byRIA) rose in all men individually into the normal range and on averageinto the normal range during treatment. Preliminary results indicatethat the average change of testosterone from baseline to week 12 wasapproximately 2-fold (250±22.3 ng/dL to 550±191.8 ng/dL). Based onadditional preliminary analysis serum estradiol (measured by LC-MS) wasreduced by approximately 30-50% (average change from baseline to week 12is 24±4.9 pg/mL to 18±9.4 pg/mL) but was not suppressed (lower limit ofdetection is 2 pg/mL) as assessed by highly sensitive LC-MS assays.

CITED AND FURTHER RELATED LITERATURE

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The various features and embodiments of the present invention, referredto in individual sections above apply, as appropriate, to othersections, mutatis mutandis. Consequently features specified in onesection may be combined with features specified in other sections, asappropriate.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

1-78. (canceled)
 79. A method for the treatment of a male patient withserum total testosterone levels below 400 ng/dl and in need of increasedtestosterone levels comprising administering to said patient aneffective amount of the compound4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile, whereinthe effective amount of the compound is from about 0.0005 mg to about5.0 mg per dose, and wherein the compound is administered according to adosing regimen having a dosing periodicity selected from about one doseonce weekly to about one dose once every month.
 80. The method of claim79 wherein said male patient has primary testicular failure.
 81. Themethod of claim 79 wherein said male patient has secondary testicularfailure with suppression of gonadotropins.
 82. The method of claim 80,wherein said testicular failure is due to endogenous defects, trauma,infection, chemotherapy, or radiation therapy.
 83. The method of claim79, wherein the testosterone level is increased by at least 10% incomparison to the testosterone level prior to administration of thecompound.
 84. The method of claim 79, wherein the testosterone level isnormalized.
 85. The method of claim 79, wherein the patient is in needof the prevention or treatment of one or more disorders selected fromthe group consisting of decreased libido, decreased spontaneouserections, erectile dysfunction, decreased fertility, loss of body hair,reduced shaving, lack of energy, fatigue, impaired cognition,depression, changes in mood, low bone mineral density, increased risk offractures, decreased muscle mass, decreased muscle strength, increasedabdominal fat mass and limited body performance capacity.
 86. The methodof claim 79, wherein the patient is in need of one or more of increasedmuscle mass and strength, a normalized body composition, a decrease inabdominal fat mass, an improved sexual function and desire, increasedfertility and increased bone mineral density.
 87. The method of claim79, wherein the effective amount of4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile is fromabout 0.01 mg to about 1.0 mg per dose.
 88. The method of claim 79,wherein the effective amount of4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile furthercomprising the administration of a loading dose of 0.3 mg.
 89. Themethod of claim 79, wherein the effective amount of4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile is orallyadministered to the patient.
 90. The method of claim 89, wherein theeffective amount of4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile is about0.1 mg per dose administered about once weekly.
 91. The method of claim79, wherein4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile isadministered according to a dosing regimen having a dosing periodicityselected from about one dose once weekly, about one dose once every 10days, about one dose once biweekly, about one dose once every 3 weeks,about one dose once every 4 weeks, and about one dose once monthly. 92.The method of claim 91, wherein4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile isadministered according to a dosing regimen having a dosing periodicityof about one dose once biweekly.
 93. The method of claim 91, wherein4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile isadministered according to a dosing regimen having a dosing periodicityof about one dose once monthly.
 94. The method of claim 79, wherein4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile, whenadministered to the patient, shows an apparent elimination half-lifechosen from one or more of at least about 14 days, at least about 20days, at least about 25 days and at least about 30 days.
 95. The methodof claim 79, wherein when administering a single dose of4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile, saiddose results in an increased effective blood concentration oftestosterone over a period of time from 3 to 30 days.
 96. The method ofclaim 95, wherein the serum concentration of testosterone is increasedby at least 10% over the serum testosterone concentration prior toadministration of the compound.
 97. The method of claim 96, whereinserum estradiol is reduced by at least about 30%.
 98. The method ofclaim 97, wherein the serum estradiol is reduced by 30-50%.
 99. Themethod of claim 98, wherein the serum estradiol is not suppressed.